Hexahydrofuro[2,3-B]furan-3-YL-N-{3-[(1,3-benzodioxol-5-ylsulfonyl)(isobutyl)amino]-1-benzyl-2-hydroxypropyl}carbamate as retroviral protease inhibitor

Abstract

Compositions comprising bis-tetrahydrofuran benzodioxyolyl sulfonamide compounds that are surprisingly effective protease inhibitors and a second antiretroviral compound are disclosed. Methods of inhibiting retrovirus proteases, in particular multi-drug resistant retrovirus proteases, methods of treating or preventing infection or disease associated with retrovirus infection in a mammal, and methods of inhibiting viral replication are also disclosed.

1. A composition comprising:
 (a) a first antiretroviral compound of the formula: 
 
       
         
           
           
               
               
           
         
          or an N-oxide, salt, ester, prodrug or metabolite thereof, in any stereoisomeric form, or a mixture thereof 
         (b) a second antiretroviral compound; and 
         (c) a pharmaceutically tolerable excipient. 
       
     
     
       2. A composition according to  claim 1 , wherein said first antiretroviral compound has the formula: 
       
         
           
           
               
               
           
         
         or an N-oxide, salt, ester, prodrug or metabolite thereof. 
       
     
     
       3. A composition according to  claim 1 , further comprising an immunomodulator. 
     
     
       4. A composition according to  claim 1 , further comprising an antibiotic. 
     
     
       5. A composition according to  claim 1 , wherein said second antiretroviral compound is a binding inhibitor, a fusion inhibitor, a co-receptor binding inhibitors, a reverse transcriptase inhibitor, a nucleoside reverse transcriptase inhibitor, a nucleotide reverse transcriptase inhibitor, a non-nucleoside reverse transcriptase inhibitor; a RNAse H inhibitor, a TAT inhibitor, an integrase inhibitor, a protease inhibitor or a glycosylation inhibitor. 
     
     
       6. A composition according to  claim 5 , wherein said second antiretroviral compound is a fusion inhibitor, a reverse transcriptase inhibitor, a nucleoside reverse transcriptase inhibitor, a non-nucleoside reverse transcriptase inhibitor; an integrase inhibitor or a protease inhibitor. 
     
     
       7. A composition according to  claim 6 , wherein said second antiretroviral compound is T20, T1249, foscarnet, a prodrug of foscarnet, AZT, 3TC, DDC, DDI, D4T, abacavir, nevirapine, delavirdine, efavirenz, TMC-125, TMC-120, capravirine, amprenavir, ritonavir, nelfinavir, saquinavir, indinavir, lopinavir or tipranavir. 
     
     
       8. A composition according to  claim 7 , wherein said second antiretroviral compound is T20, foscarnet, AZT, 3TC, DDC, DDI, D4T, abacavir, nevirapine, delavirdine, efavirenz, capravirine, amprenavir, ritonavir, nelfinavir, saquinavir, indinavir, lopinavir or tipranavir. 
     
     
       9. A kit comprising:
 (a) a first antiretroviral compound of the formula: 
 
       
         
           
           
               
               
           
         
          or an N-oxide, salt, ester, prodrug or metabolite thereof, in any stereoisomeric form, or a mixture thereof; 
         (b) a second antiretroviral compound; 
         (c) instructions for administering said first antiretroviral compound, said second antiretroviral compound and optional components simultaneously, separately or sequentially; and 
         (d) a pharmaceutically tolerable excipient. 
       
     
     
       10. A kit according to  claim 9 , further comprising an immunomodulator. 
     
     
       11. A kit according to  claim 9 , further comprising an antibiotic. 
     
     
       12. A kit according to  claim 9 , wherein said first antiretroviral compound has the formula: 
       
         
           
           
               
               
           
         
         or an N-oxide, salt, ester, prodrug or metabolite thereof. 
       
     
     
       13. A kit according to  claim 9 , wherein said second antiretroviral compound is a binding inhibitor, a fusion inhibitor, a co-receptor binding inhibitors, a reverse transcriptase inhibitor, a nucleoside reverse transcriptase inhibitor, a nucleotide reverse transcriptase inhibitor, a non-nucleoside reverse transcriptase inhibitor; a RNAse H inhibitor, a TAT inhibitor, an integrase inhibitor, a protease inhibitor or a glycosylation inhibitor. 
     
     
       14. A kit according to  claim 13 , wherein said second antiretroviral compound is a fusion inhibitor, a reverse transcriptase inhibitor, a nucleoside reverse transcriptase inhibitor, a non-nucleoside reverse transcriptase inhibitor; an integrase inhibitor or a protease inhibitor. 
     
     
       15. A kit according to  claim 14 , wherein said second antiretroviral compound is T20, T1249, foscarnet, a prodrug of foscarnet, AZT, 3TC, DDC, DDI, D4T, abacavir, nevirapine, delavirdine, efavirenz, TMC-125, TMC-120, capravirine, amprenavir, ritonavir, nelfinavir, saquinavir, indinavir, lopinavir or tipranavir. 
     
     
       16. A kit according to  claim 15 , wherein said second antiretroviral compound is T20, foscarnet, AZT, 3TC, DDC, DDI, D4T, abacavir, nevirapine, delavirdine, efavirenz, capravirine, amprenavir, ritonavir, nelfinavir, saquinavir, indinavir, lopinavir or tipranavir. 
     
     
       17. A method of treating a retroviral infection in a mammal, comprising the step of:
 administering to said mammal an effective amount of said composition according to  claim 1 . 
 
     
     
       18. A method according to  claim 17 , wherein said mammal is a human. 
     
     
       19. A method according to  claim 17 , wherein said composition further comprises a pharmaceutically tolerable excipient. 
     
     
       20. A method according to  claim 17 , wherein said composition further comprising an immunomodulator. 
     
     
       21. A method according to  claim 17 , wherein said composition further comprising an antibiotic. 
     
     
       22. A method according to  claim 17 , wherein said first antiretroviral compound has the formula: 
       
         
           
           
               
               
           
         
       
       or an N-oxide, salt, ester, prodrug or metabolite thereof. 
     
     
       23. A method according to  claim 17 , wherein said second antiretroviral compound is a binding inhibitor, a fusion inhibitor, a co-receptor binding inhibitors, a reverse transcriptase inhibitor, a nucleoside reverse transcriptase inhibitor, a nucleotide reverse transcriptase inhibitor, a non-nucleoside reverse transcriptase inhibitor; a RNAse H inhibitor, a TAT inhibitor, an integrase inhibitor, a protease inhibitor or a glycosylation inhibitor. 
     
     
       24. A method according to  claim 23 , wherein said second antiretroviral compound is a fusion inhibitor, a reverse transcriptase inhibitor, a nucleoside reverse transcriptase inhibitor, a non-nucleoside reverse transcriptase inhibitor; an integrase inhibitor or a protease inhibitor. 
     
     
       25. A method according to  claim 24 , wherein said second antiretroviral compound is T20, T1249, foscarnet, a prodrug of foscarnet, AZT, 3TC, DDC, DDI, D4T, abacavir, nevirapine, delavirdine, efavirenz, TMC-125, TMC-120, capravirine, amprenavir, ntonavir, nelfinavir, saquinavir, indinavir, lopinavir or tipranavir. 
     
     
       26. A method according to  claim 25 , wherein said second antiretroviral compound is T20, foscarnet, AZT, 3TC, DDC, DDI, D4T, abacavir, nevirapine, delavirdine, efavirenz, capravirine, amprenavir, ritonavir, nelfinavir, saquinavir, indinavir, lopinavir or tipranavir. 
     
     
       27. A method according to  claim 17 , wherein said infection or disease associated with retrovirus infection is a human immunodeficiency virus. 
     
     
       28. A method according to  claim 27 , wherein said human immunodeficiency virus is a multiple drug-resistant strain. 
     
     
       29. A method of inhibiting retroviral replication, comprising the step of:
 contacting a retrovirus with an effective amount of said composition according to  claim 1 . 
 
     
     
       30. A method according to  claim 29 , wherein said composition further comprises a pharmaceutically tolerable excipient. 
     
     
       31. A method according to  claim 29 , wherein said composition further comprising an immunomodulator. 
     
     
       32. A method according to  claim 29 , wherein said composition further comprising an antibiotic. 
     
     
       33. A method according to  claim 29 , wherein said first antiretroviral compound has the formula: 
       
         
           
           
               
               
           
         
       
       or an N-oxide, salt, ester, prodrug or metabolite thereof. 
     
     
       34. A method according to  claim 29 , wherein said second antiretroviral compound is a binding inhibitor, a fusion inhibitor, a co-receptor binding inhibitors, a reverse transcriptase inhibitor, a nucleoside reverse transcriptase inhibitor, a nucleotide reverse transcriptase inhibitor, a non-nucleoside reverse transcriptase inhibitor; a RNAse H inhibitor, a TAT inhibitor, an integrase inhibitor, a protease inhibitor or a glycosylation inhibitor. 
     
     
       35. A method according to  claim 34 , wherein said second antiretroviral compound is a fusion inhibitor, a reverse transcriptase inhibitor, a nucleoside reverse transcriptase inhibitor, a non-nucleoside reverse transcriptase inhibitor; an integrase inhibitor or a protease inhibitor. 
     
     
       36. A method according to  claim 35 , wherein said second antiretroviral compound is T20, T1 249, foscarnet, a prodrug of foscarnet, AZT, 3TC, DDC, DDI, D4T, abacavir, nevirapine, delavirdine, efavirenz, TMC-125, TMC-120, capravirine, amprenavir, ritonavir, nelfinavir, saquinavir, indinavir, lopinavir or tipranavir. 
     
     
       37. A method according to  claim 36 , wherein said second antiretroviral compound is T20, foscarnet, AZT, 3TC, DDC, DDI, D4T, abacavir, nevirapine, delavirdine, efavirenz, capravirine, amprenavir, ritonavir, nelfinavir, saquinavir, indinavir, lopinavir or tipranavir. 
     
     
       38. A method according to  claim 29 , wherein said retrovirus is a human immunodeficiency virus. 
     
     
       39. A method according to  claim 38 , wherein said human immunodeficiency virus is a multiple drug-resistant strain. 
     
     
       40. A method of inhibiting a protease of a retrovirus in a mammal infected with said retrovirus, comprising the step of:
 administering a protease inhibiting amount of said composition according to  claim 1 . 
 
     
     
       41. A method according to  claim 40 , wherein said mammal is a human. 
     
     
       42. A method according to  claim 40 , wherein said composition further comprises a pharmaceutically tolerable excipient. 
     
     
       43. A method according to  claim 40 , wherein said composition further comprising an immunomodulator. 
     
     
       44. A method according to  claim 40 , wherein said composition further comprising an antibiotic. 
     
     
       45. A method according to  claim 40 , wherein said first antiretroviral compound has the formula: 
       
         
           
           
               
               
           
         
       
       or an N-oxide, salt, ester, prodrug or metabolite thereof. 
     
     
       46. A method according to  claim 40 , wherein said second antiretroviral compound is a binding inhibitor, a fusion inhibitor, a co-receptor binding inhibitors, a reverse transcriptase inhibitor, a nucleoside reverse transcriptase inhibitor, a nucleotide reverse transcriptase inhibitor, a non-nucleoside reverse transcriptase inhibitor; a RNAse H inhibitor, a TAT inhibitor, an integrase inhibitor, a protease inhibitor or a glycosylation inhibitor. 
     
     
       47. A method according to  claim 46 , wherein said second antiretroviral compound is a fusion inhibitor, a reverse transcriptase inhibitor, a nucleoside reverse transcriptase inhibitor, a non-nucleoside reverse transcriptase inhibitor; an integrase inhibitor or a protease inhibitor. 
     
     
       48. A method according to  claim 47 , wherein said second antiretroviral compound is T20, T1249, foscarnet, a prodrug of foscarnet, AZT, 3TC, DDC, DDI, D4T, abacavir, nevirapine, delavirdine, efavirenz, TMC-125, TMC-120, capravirine, amprenavir, ritonavir, nelfinavir, saquinavir, indinavir, lopinavir or tipranavir. 
     
     
       49. A method according to  claim 48 , wherein said second antiretroviral compound is T20, foscarnet, AZT, 3TC, DDC, DDI, D4T, abacavir, nevirapine, delavirdine, efavirenz, capravirine, amprenavir, ritonavir, nelfinavir, saquinavir, indinavir, lopinavir or tipranavir. 
     
     
       50. A method according to  claim 40 , wherein said retrovirus is a human immunodeficiency virus. 
     
     
       51. A method according to  claim 50 , wherein said human immunodeficiency virus is a multiple drug-resistant strain.